Genome-wide scan on total serum IgE levels identifies FCER1A as novel susceptibility locus

Abstract

High levels of serum IgE are considered markers of parasite and helminth exposure. In addition, they are associated with allergic disorders, play a key role in anti-tumoral defence, and are crucial mediators of autoimmune diseases. Total IgE is a strongly heritable trait. In a genome-wide association study (GWAS), we tested 353,569 SNPs for association with serum IgE levels in 1,530 individuals from the population-based KORA S3/F3 study. Replication was performed in four independent population-based study samples (total n = 9,769 individuals). Functional variants in the gene encoding the alpha chain of the high affinity receptor for IgE (FCER1A) on chromosome 1q23 (rs2251746 and rs2427837) were strongly associated with total IgE levels in all cohorts with P values of 1.85 x 10(-20) and 7.08 x 10(-19) in a combined analysis, and in a post-hoc analysis showed additional associations with allergic sensitization (P = 7.78 x 10(-4) and P = 1.95 x 10(-3)). The "top" SNP significantly influenced the cell surface expression of FCER1A on basophils, and genome-wide expression profiles indicated an interesting novel regulatory mechanism of FCER1A expression via GATA-2. Polymorphisms within the RAD50 gene on chromosome 5q31 were consistently associated with IgE levels (P values 6.28 x 10(-7)-4.46 x 10(-8)) and increased the risk for atopic eczema and asthma. Furthermore, STAT6 was confirmed as susceptibility locus modulating IgE levels. In this first GWAS on total IgE FCER1A was identified and replicated as new susceptibility locus at which common genetic variation influences serum IgE levels. In addition, variants within the RAD50 gene might represent additional factors within cytokine gene cluster on chromosome 5q31, emphasizing the need for further investigations in this intriguing region. Our data furthermore confirm association of STAT6 variation with serum IgE levels.

Figure 1. Results of the KORA S3/F3 500 K analysis.

a) Genome-wide association study of chromosomal loci for IgE levels: the analysis is based on a population-based sample of 1530 persons. The x-axis represents the genomic position of 353,569 SNPs, and the y-axis shows −log10 (P value). b) Quantile-quantile plot of P values: Each black dot represents an observed statistic (defined as the −log10( P value)) versus the corresponding expected statistic. The line corresponds to the null distribution.

Figure 2. Expression of the FCER1 alpha chain on IgE-stripped basophils.

PBMCs were isolated from individuals displaying high sIgE levels and FCER1 alpha chain expression was measured after stripping IgE from its receptor by lactic acid buffer incubation by FACS. Results are expressed as mean fluorescence intensity for FCER1A in the basophile gate. Significance was calculated using the Student's-t-test.

Figure 3. P value and pairwise linkage disequilibrium diagram of the region on chromosome 1q23, area of FCER1A (panel A), and chromosome 5q31, area of RAD50 (panel B).

Pairwise LD, measured as D', was calculated from KORA S3/F3 500 K. Shading represents the magnitude of pairwise LD with a white to red gradient reflecting lower to higher D' values. Gene regions are indicated by colored bars. P value diagram: The x-axis represents the genomic position. The y-axis shows −log10 (P values) of KORA S3/F3 500 K (blue), KORA S4 (black), GINI (yellow), LISA (green), ISAAC (orange), combined replication samples (red).